In this revised application for a Mentored Patient Oriented Research Career Development Award, the candidate, Smit S. Sinha, will develop expertise in the psychoneuroendocrinology of anxiety, with emphasis on the endogenous opioid system and its interactions with the hypothalamic-pituitary-adrenal axis in panic disorder. The endogenous opioid system is an integral aspect of the human stress response, and exerts widespread regulatory influence on specific neurotransmitter and neurohormonal systems located in key brain regions thought to regulate stress, anxiety and panic states. Of particular relevance to panic disorder is the evidence for opioid regulation of carbon dioxide sensitivity, which is abnormally heightened in panic and is a strong biological marker of the illness. Opioids also regulate attachment and separation behaviors, disruptions of which are strongly implicated in the development and maintenance of the illness. This proposal will also investigate HPA axis function in panic disorder. Disruptions of HPA function, particularly abnormal and increased central corticotropin releasing hormone (CRH) drive, have been implicated in the pathogenesis of major depressive disorder and PTSD. However, whether panic disorder involves central CRH dysregulation is not known. This is despite the prominent role of CRH in anxiogenesis and respiratory regulation. Preliminary data from the candidate and mentors suggest that panic disorder involves significant abnormalities in the opioid system and the CRH system. The candidate's research plan will 1. Assess the central functioning of both the endogenous opioid system and the CRH system with naloxone and metyrapone administration, respectively 2. Relate central opioid activity and CRH activity to CO2 sensitivity 3. Address functional interactions between these systems and 4. Assess the effects of medication treatment on these systems. The career development activities build on Dr. Sinha's background in clinical research and capitalizes on the resources of Columbia University. The overall goals are to acquire skills in the psychoneuroendocrinology of anxiety and stress with application to the pathophysiology of panic disorder. The comprehensive educational plan provides expert mentorship and didactic instruction in the key areas applied in the research plan: 1) neuroendocrinology 2) psychophysiology 3)research design and statistics and 4) clinical trials methodology. [unreadable] [unreadable]